Azabicycloalkyl urea compounds

ABSTRACT

N-aroyl-N&#39;&#39;-(3-azabicycloalkyl) ureas of the formula : WHEREIN N IS 1, 2 OR 3. These compounds possess fibrinolytic and platelet stickiness decreasing properties, decrease the capillary permeability, increase their resistance and improve the microcirculation.

United States Patent [151 3,696,1 17 Beregi et al. 51 Oct. 3, 1972 [541AZABICYCLOALKYL UREA [56] References Cited COMPOUNDS 72 I L I Be B l SUNIIED STATES PATENTS entors: asz 0 r i S y l l Pierre g 3,491,1131/1970 Schenker et al. ..260/326.l

Pierre Desnoyers, Fontenay-aux- Primary Examiner-Alex Mazel Roses an ofFrance Assistant Examiner-Joseph A. Narcavage [73] Assignee: Societe ennom collectif Science Attorney-Gordon W. Hueschen and Talivaldis Cepu-Union et Rie, Societe Francaise de ritiS Recherche Medicale, Suresnes,France [5 7] [22] Filed: Sept. 28, 1970 N-ar0yl'N'-( 3-azabicycloalkyl)ureas of the formula 21 Appl: N0; 76,204 M) HaC-QC 0NH-C 0--NH CH1) D I[30] Forelgn Application Priority ata wherein n is 2 or 3 March 10, 1969Great Britain ..48,645/69 These compounds possess fibrinolytic andplatelet stickiness decreasing properties, decrease the capillary [52]US. Cl ..260/326.36 422/273 permeability increase their resistance andimprove Int. Clthe microcirculatio Field of Search ..260/326.3

2 Claims, No Drawings AZABICYCLOALKYL UREA COMPOUNDS The presentinvention provides N-aroyl-N'-(3-azal: icycloalkyl) areas of the generalformula wherein n is an integer from 1 to 3 inclusive.

In the above general formula the radical of the forrepresents thefollowing 3-azabicyclo alkane radicals of the formulae The inventionalso includes the salts, especially the physiologically tolerable salts,of the above compounds.

The N-aroyl-N'-(3-azabicycloalkyl) ureas of the present invention arenew compounds and can be prepared by reacting para-toluoyl isocyanatewith a N- amino-3-azabicyclo alkane of the general formula HzN-N Hz) 1:

VI wherein n has the meaning given above.

The N-amino-3-azabicyclo alkanes used as starting material may beprepared by means of the process of 1B. Wright, RE. Willette J. Med. andPharm. Chem., 5, 819 (1962), which involves nitrosating a 3- azabicycloalkane and reducing the resulting N-nitroso derivative with lithiumaluminum hydride.

The 3-azabicyclo alkanes employed in this invention may be obtained byconverting, respectively, the known cyclopentane, eyclobutane andcyclopropane dicarboxylic acids into imides by the method of H. Najer,R. Giudicelli Bull. Soc. Chim. France, 1593 (1962), and finallysubmitting the imides to reduction by means of lithium aluminum hydride,following the method described by R. Griot, Helv. Chim. Acta. 42, 67(1959).

The compounds of the invention may be readily obtained in the form oftheir salts with suitable acids, especially acids yieldingphysiologically tolerable salts. Among the acids that may be used,hydrochloric, hydrobromic, sulphonic, acetic, malonic, maleic, fumaric,tartaric and malic acids may be mentioned.

The present invention also includes the salts formed with an alkalimetal hydroxide, an alkaline earth metal hydroxide, an alkali metalcarbonate, an alkaline earth metal carbonate and an alkali metalbicarbonate.

The following examples illustrate the present invention, all parts beingby weight and melting points being determined on a Kofler block (K), oron a Kotler heater under a microscope (MK).

EXAMPLE 1 N-para-toluoyl-N'-[3-azabicyclo (3,3,0) oct-3-yl] urea To asolution of 8 parts of para-toluoyl isocyanate in parts of anhydrousbenzene there were added during 20 minutes 6.3 parts ofN-amino-3-azabicyclo (3,3,0) octane dissolved in 40 parts of benzene.The mixture was stirred for 2 hours. The resulting solution crystallizedon cooling. 5.75 parts of crude product were obtained and a further 11.5parts were obtained by evaporating to dryness the remaining solution.

The combined crude products yielded by recrystallization in 80 parts ofisopropanol, 10.6 parts of N- para-toluoyl-N'-[3-azabicyclo (3,3,0)oct-3-yl] urea, M.P. (K) 173 C M.P. (MK) to 166 C.

EXAMPLES 2 t5 3 By the same process as described in Example 1, the

following urea compounds were obtained 2.N-para-toluoyl-N'-[3-azabicyclo (3,2,0) hept-3-yl] urea, starting fromparatoluoyl isocyanate and N- amino-3-azabicyclo (3,2,0) heptane. 3.N-para-toluoyl-N'-[3-azabicyclo (3,1,0) hex-3-yl] urea, starting fromparatoluoyl isocyanate and N- amino-3-azabicyclo (3,1,0) hexane.

The new compounds of the present invention, and their physiologicallytolerable salts possess valuable therapeutic and pharmacologicalproperties, especially fibrinolytic and platelet stickiness decreasingproperties; they decrease the capillary permeability, increase theirresistance and improve the microcirculation.

Their toxicity is very weak and the LD studied in mice is exceeding 3g/kg per oral route.

The measure of the plasmatic euglobulin lysis time described asmicromethod by von Kaulla (Thromb. Diath. Haemorrhag. 15 284 (1966)) wasused to determine the fibrinolytic potential. It was noted that theproducts administered to the rat at the dose of 200 mg/kg P.O. increasethe euglobulin lysis time of 12 to 16 percent after 1 to 2 hours.

The activity on the platelet stickiness was evidenced by the method ofE.W. Salzmann (J. Lab. Clin. Med. 62, 724 (1963)). It was noted that thecompounds of the invention, administered at the dose of 200 mg/kg per osdecrease the stickiness of the thrombocytes by 25 to 30 percent, andinhibit the stickiness increasing action of adenosine diphosphate.

The activity on the capillary permeability was observed by the method ofAmbrose and Eds (J. Pharm. Exp. Therap. 90, 359 (1947)). It was noted atime increasing of the apparition of the coloration in comparison withthe untreated animals. Parrots method was used to measure the capillaryresistance (CR. Soc. Biol. 140. 750 (1946)). It was found that compoundsof the present invention increase considerably the capillary resistance.

The low toxicity and the properties here-above described pennit the useof the new compounds in therapy, especially in the prevention and in thetreatment of the thromboembolic disease, angiopathies and capillarybrittleness.

The invention also provides pharmaceutical compositions containing acompound of the general Formula I or one of its physiologicallytolerable salts in admixture or conjunction with suitable pharmaceuticalcarriers, such as, for example, distilled water, glucose, lactose,starch, talc, magnesium stearate, cocoa butter. These pharmaceuticalcompositions may be form of tablets, dragees, capsules, suppositories orinjectable solutions, and may be administered by oral, rectal orparenteral route at the doses of 50 to 500 mg l to 5 times per day.

WHAT WE CLAIM IS 1. A compound selected from the group consisting of A.N-aroyl-N-(3-azabicycloalkyl) ureas of the general formula

2. A compound of claim 1 which is N-para-toluoyl-N''-(3-azabicyclo(3,3,0) oct-3-yl) urea.